The purpose of this study is to define the cellular and molecular bases of the different human primary immunodeficiency disorders so that permanent and/or more effective therapy can be developed. During the last reporting period, a previously undescribed molecular cause of human severe combined immunodeficiency (Janus kinase 3 or Jak3 deficiency) was discovered in patients seen under this protocol on the Duke University Clinical Research Unit by the P.I. and her associates. During the current year we have identified a total of 9 patients with Jak3 deficiency and these studies are continuing. We have continued to be the major U.S. referral center for patients with genetically-determined immunodeficiency, in part because of our experience and success in haploidentical marrow stem cell transplantation for human severe combined immunodeficiency. During the current reporting period, we performed 19 such stem cell transplants in patients with primary immunodeficiency. The creation of human SCID haploidentical bone marrow stem cell chimeras has allowed us a unique opportunity to examine the cellular and molecular bases of human thymic education. Future plans for this protocol are to continue to examine patients with primary immunodeficiency for their fundamental abnormalities so that gene therapy might be accomplished when the technology for this becomes perfected. We will continue to characterize all such patients at a cellular level so that consistent phenotypic and functional patterns can be used as an aid in predicting underlying molecular defects, as it did in the case of Jak3 deficiency. Our plans also include the continued study of T and B cell ontogeny, MHC restriction, and tolerance induction in the 60 surviving human SCID bone marrow stem cell chimeras that we have developed over the past 14.5 years. Bone marrow stem cell transplantation is currently the most successful therapy for all forms of human SCID (78% success rate at this Institution) and will continue to be so until gene therapy becomes perfected. This CRU protocol has permitted us to become a world leader in this type of transplantation. However, since T cell-depleted haploidentical marrow transplantation was only developed 15 years ago, the long term extent of immune reconstitution is unknown and can only be known through continued and careful longitudinal immunologic studies in these rare and informative infants and children.